It is unfortunate, but progress in understanding the biology of prostate cancer has been slow because of 1) our limited understanding of the factors that control the growth and differentiation of the prostate gland, 2) the inherent difficulties involved in studying how changes in genotype contribute to such a heterogeneous disease in a heterogeneous population, and 3) the paucity of animal models that faithfully mimic, both temporally and spatially, the progressive stages associated with clinical prostate cancer. Clearly, these observations underscore the need to develop, characterize and disseminate relevant model systems with defined genetic backgrounds that accurately and reproducibly display heritable, and progressive prostate malignancies. Hence, the long term goal of this competing continuation application by the Baylor College of Medicine (BCM) Texas A&M University (TAMU) and University of Western Ontario (UWO) group is to leverage our expertise in the generation, characterization and application of germ-line mouse models and build on our record of achievement in prostate cancer research to function as an integral component of the NCI Mouse Models for Human Cancers Consortium (MMHCC). In this application, we present seven integrated projects (five at BCM, one at TAMU and one at UWO) all designed to generate, characterize and disseminate important genetically engineered mouse models in order to (a) facilitate identification and examination of molecular mechanisms responsible for initiation, progression and metastasis of prostate cancer and (b) hasten the development and translation of efficacious strategies for prevention, diagnosis and therapy. The projects will attempt to establish new models to investigate genomic instability, metastasis, cell death, cell growth, provide real time non invasive imaging, and understand the role of the microenvironment and deregulated growth factor signaling in prostate cancer.